ABSTRACT
The phase 3 MOMENTUM study (NCT04173494) of the ACVR1/JAK1/JAK2 inhibitor momelotinib (MMB) vs. danazol (DAN) in patients with myelofibrosis (MF) previously treated with a JAK inhibitor (JAKi) met the primary endpoint and all key secondary endpoints at week 24 (W24). We provide updated results from week 48 assessments. Eligible patients had primary or post-ET/ PV MF;DIPSS high, Int-2, or Int-1 risk;Total Symptom Score (TSS) >=10;haemoglobin (Hb) <10 g/dL;platelets >=25 x 109/L;prior JAKi for >=90 days (>=28 days if red blood cell [RBC] transfusions >=4 units in 8 weeks or grade 3/4 thrombocytopenia/anaemia/ hematoma);and palpable spleen >=5 cm. Randomisation was 2:1 to MMB 200 mg/day or DAN 600 mg/day for 24 weeks, followed by open-label (OL) MMB. Week 48 endpoints included durations of response (TSS, transfusion independence [TI], splenic) and overall and leukaemia-free survival (OS, LFS). As of 17 May 2022, 93/130 (72%) MMB -> MMB and 41/65 (63%) DAN -> MMB patients received OL MMB;mean MMB durations were 48 weeks and 24 weeks, respectively. Analyses for W24 responders showed the following: of TSS responders, 31/32 (97%) MMB -> MMB and 6/6 DAN -> MMB patients had TSS < baseline;of TI responders, 36/40 (90%) and 10/13 (77%) had no RBC transfusions or Hb <8 g/dL;and of spleen responders, all patients had splenic volume < baseline. In the OL phase, the most common grade >=3 treatment-emergent adverse events (TEAEs) were thrombocytopenia (MMB -> MMB, 9%;DAN -> MMB, 15%) and anaemia (MMB -> MMB, 9%;DAN -> MMB, 2%). Grade >=3 infections occurred in 19% of MMB -> MMB and 10% of DAN -> MMB patients, including grade >=3 (nonfatal) COVID-19. Peripheral neuropathy (PN) occurred in 2% of patients in each arm, and none discontinued MMB due to PN. TEAEs led to MMB discontinuation in 18% (MMB -> MMB) vs. 10% (DAN -> MMB). A trend towards improved OS up to W24 was previously observed with MMB vs. DAN (hazard ratio [HR], 0.506;p = 0.0719);after all patients crossed over to OL MMB, OS and LFS curves for both arms converged (HR, 0.945, 95% CI, 0.528-1.693;HR, 0.830, 95% CI, 0.473-1.4555). Sixty of 81 (74%) MMB -> MMB and 29 of 43 (67%) DAN -> MMB patients with baseline platelets <=150 x 109/L entered the OL phase. Efficacy and safety results in thrombocytopenic subgroups in the OL period were consistent with the intent-to- treat (ITT) population. OL MMB maintained symptom, TI, and spleen responses with continued good survival and safety in the ITT and low platelet populations. MMB may address an unmet need in anaemic patients with MF.
ABSTRACT
Category: Outcomes of treatment (including chemotherapy, chemo-RT and RT) Purpose: To describe the five-year treatment outcomes of patients with anal squamous carcinoma treated with concurrent chemoradiotherapy (CRT) specified with volumetric modulated arc radiotherapy (VMAT) at a Welsh tertiary referral centre. Methods and materials: A total of 80 anal cancer patients received radical CRT between 2016 and 2021. CRT consisted of 50.4 Gy/28 fractions (1.8 Gy daily) to the gross tumour volumes (GTV), and the elective nodes were prescribed 40 Gy/28 fractions (1.42 Gy/daily) for patients having a cT1/2N0M0. Patients with cT3-T4/N0-N1a-cM0 were prescribed 53.2 Gy/28 fractions (1.9 Gy daily) to the GTV;gross nodal volumes were prescribed 50.4 Gy/28 fractions (1.8 Gy daily) if sized <=3 cm or 53.2 Gy/28 fractions (1.9 Gy daily) if >3 cm;elective nodal areas were given 40 Gy/28 fractions (1.42 Gy daily). Mitomycin and capecitabine were administered concurrently. The primary outcome was colostomy-free survival (CFS). Secondary outcomes were cancer-specific survival (CSS), disease-free survival (DFS), overall survival (OS) and adverse effects. Result(s): Median follow-up was 31.3 months (3-61). The five-year CFS was 94.3% (95% CI: 50.0%-96.5%). The five-year CSS, DFS and OS were 92% (95% CI: 60.5-95%), 86.7% (95% CI: 58-89%) and 67.9% (95% CI: 56.6-75.1%) respectively. A total of four (5%) local recurrences and one (1.3%) regional recurrence was observed. A total of seven patients (8.7%) had distant metastasis (liver was a frequent site;57.1%);three patients (3.7%) died of COVID pneumonia. Late toxicities were as: vaginal stenosis (6.3%), sexual dysfunction (1.25%) and urine incontinence (1.25%). Second malignancies were as: lung (2.5%), gastric (1.3%), pancreatic cancer (1.3%) and cholangiocarcinoma (1.3%). Conclusion(s): Our experience supports the use of VMAT on a routine basis for the CRT of anal squamous cell carcinoma. Copyright © 2022
ABSTRACT
Background and objectives: Patients with muscle-invasive bladder cancer (MIBC) often experience a waiting period before radical surgery for numerous reasons; however, the COVID-19 outbreak has exacerbated this problem. Therefore, it is necessary to discuss the impact of the unavoidable time of surgical delay on the outcome of patients with MIBC. Methods: In all, 165 patients from high-volume centers with pT2-pT3 MIBC, who underwent radical surgery between January 2008 and November 2020, were retrospectively evaluated. Patients' demographic and pathological information was recorded. Based on the time of surgical delay endured, patients were divided into three groups: long waiting time (> 90 days), intermediate waiting time (30-90 days), and short waiting time (≤ 30 days). Finally, each group's pathological characteristics and survival rates were compared. Results: The median time of surgical delay for all patients was 33 days (interquartile range, IQR: 16-67 days). Among the 165 patients, 32 (19.4%) were classified into the long waiting time group, 55 (33.3%) into the intermediate waiting time group, and 78 (47.3%) into the short waiting time group. The median follow-up period for all patients was 48 months (IQR: 23-84 months). The median times of surgical delay in the long, intermediate, and short waiting time groups were 188 days (IQR: 98-367 days), 39 days (IQR: 35-65 days), and 16 days (IQR: 12-22 days), respectively. The 5-year overall survival (OS) rate for all patients was 58.4%, and that in the long, intermediate, and short waiting time groups were 35.7%, 61.3%, and 64.1%, respectively (P = 0.035). The 5-year cancer-specific survival (CSS) rates in the long, intermediate, and short waiting time groups were 38.9%, 61.5%, and 65.0%, respectively (P = 0.042). The multivariate Cox regression analysis identified age, time of surgical delay, pT stage, and lymph node involvement as independent determinants of OS and CSS. Conclusion: In patients with pT2-pT3 MIBC, the time of surgical delay > 90 days can have a negative impact on survival.
ABSTRACT
Purpose: To report final results of a clinical trial of APBI using intensity modulated radiotherapy (IMRT) to deliver 27 Gy in 5 daily fractions following breast conserving surgery (BCS) prospectively designed to assess the efficacy and cosmetic outcomes of a oneweek, APBI regimen among women with early breast cancer. Material(s) and Method(s): Women >= 50 years, with lymph nodenegative, ER positive, HER-2 negative breast cancer or ductal carcinoma in situ (DCIS), <= 3cm diameter, following BCS with margins >= 2mm, and excellent or good baseline cosmesis received 27 Gy in 5 daily fractions to the seroma plus 1 cm CTV and 0.7 cm PTV margins. Clinical photographs, patient and provider cosmetic scores, breast fibrosis, telangiectasia and pain were collected prospectively, prior to RT and at 6 weeks, 1 and 2 years after RT. The primary endpoint was the proportion of women who retained Excellent or Good cosmesis at 2 years using the EORTC Cosmetic Rating System. Cosmetic failure was deterioration from Excellent or Good to Fair or Poor. A panel of 5 radiation oncologists independently assessed the cosmetic photographs. Secondary endpoints were rates and grades of breast fibrosis, telangiectasia, breast pain, ipsilateral breast tumour recurrence (IBRT), overall (OS), breast cancer-specific survival (BCSS) and subsequent mastectomy. Efficacy outcomes were assessed at clinic visits and by review of charts. ClinicalTrials.gov registration: NCT02681107. Result(s): A total of 298 patients were treated between April 25, 2016, and October 31, 2019. At a median follow-up of 48 months, the four-year OS was 98.5% (95% CI 96.1% - 99.5%) and BCSS was 99.7% (95% CI 97.6% - 99.9%). The four-year IBRT rate was 3.3% (95% CI 1.1% - 6.4%). There were 10 contralateral breast events for a four-year rate of 3.9% (95% CI 2.2% - 6.9%). There were 10 ipsilateral and six contralateral mastectomies. Two patients died of unrelated causes prior to two years;79 patients declined inclinic attendance due to COVID or competing comorbidities and 217 women had two-year cosmetic photographs and clinical assessments performed. Consensus of the photo-panel cosmesis at baseline was: Excellent: n=116 (53%), Good: n=102 (47%), Fair: n=1 (0.5%) and Poor: n=0. Consensus overall cosmesis at two years was: Excellent: n= 141 (65%), Good: n=78 (35%), Fair: n=0 and Poor: n=0. Most patients had either improved (n=168;77%) or no change (n=43;20%) in cosmesis at two years. No patient had cosmetic failure but 6 (3%) had a change from Excellent to Good at two years. Most patients reported either no (79%) or mild (21%) pain, with no moderate or severe pain. Two patients (0.9%) had Grade 2 fibrosis and five patients (2%) had visible telangiectasia that did not detract from overall cosmesis. Conclusion(s): APBI using 27 Gy in 5 fractions using a conformal IMRT technique, achieved excellent two-year cosmesis with minimal toxicity. The IBRT risk was comparable to the contralateral new breast cancer risk and to local recurrence rates of recently published early breast cancer trials. Copyright © 2022 Elsevier Ireland Ltd. This is an open access article under the CC-BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
ABSTRACT
Background: AAP or ENZ added to ADT improves outcomes for mHSPC. Any benefit of combining ENZ & AAP in this disease setting is uncertain. Methods: STAMPEDE is a multi-arm, multi-stage (MAMS), platform protocol conducted at 117 sites in the UK & Switzerland. 2 trials with no overlapping controls randomised mHSPC patients (pts) 1:1 to ADT +/- AAP (1000mg od AA + 5mg od P) or AAP + ENZ (160mg od). Treatment was continued to progression. From Jan 2016 docetaxel 75mg/m2 3-weekly with P 10mg od was permitted + ADT. Using meta-analysis methods, we tested for evidence of a difference in OS and secondary outcomes (as described previously: failure-free, metastatic progression-free, progression-free & prostate cancer specific survival) across the 2 trials using data frozen 3 Jul 2022. All confidence intervals (CI) 95%. Restricted mean survival times (RMST) restricted to 84 months (m). Results: Between Nov 2011 & Jan 2014, 1003 pts were randomised ADT +/- AAP & between Jul 2014 & Mar 2016, 916 pts were randomised ADT +/- AAP + ENZ. Randomised groups were well balanced across both trials. Pt cohort: age, median 68 years (yr), IQR 63, 72;PSA prior to ADT, median 95.7 ng/ml, IQR 26.5, 346;de novo 94%, relapsed after radical treatment, 6%. In AAP + ENZ trial, 9% had docetaxel + ADT. OS benefit in AAP + ENZ trial, HR 0.65 (CI 0.55‒0.77) p = 1.4×10-6;in AAP trial, HR 0.62 (0.53, 0.73) p = 1.6×10-9. No evidence of a difference in treatment effect (interaction HR 1.05 CI 0.83‒1.32, p = 0.71) or between-trial heterogeneity (I2 p = 0.70). Same for secondary end-points. % (CI) of pts reporting grade 3-5 toxicity in 1st 5 yr: AAP trial, ADT: 38.5 (34.2-42.8), + AAP: 54.4 (50.0-58.8);AAP + ENZ trial, ADT: 45.2 (40.6 – 49.8), + AAP + ENZ: 67.9 (63.5 – 72.2);most frequently increased with AAP or AAP + ENZ = liver derangement, hypertension. At 7 yr in AAP trial (median follow-up: 95.8m), % (CI) pts alive with ADT: 30 (26, 34) versus with ADT + AAP: 48 (43, 52);RMST: ADT: 50.4m, ADT + AAP: 60.6m, p = 6.6 x 10-9. Conclusions: ENZ + AAP need not be combined for mHSPC. Clinically important improvements in OS when adding AAP to ADT are maintained at 7 yr. Clinical trial identification: NCT00268476. Legal entity responsible for the study: Medical Research Council Clinical Trials Unit at University College London. Funding: Cancer Research UK, Medical Research Council, Janssen, Astellas. Disclosure: G. Attard: Financial Interests, Personal, Invited Speaker: Janssen, Astellas, AstraZeneca;Financial Interests, Personal, Advisory Board: Janssen, Astellas, Novartis, Bayer, AstraZeneca, Pfizer, Sanofi, Sapience, Orion;Financial Interests, Personal, Royalties, Included in list of rewards to discoverers of abiraterone: Institute of Cancer Research;Financial Interests, Institutional, Research Grant: Janssen, Astellas;Non-Financial Interests, Principal Investigator: Janssen, Astellas;Non-Financial Interests, Advisory Role: Janssen, AstraZeneca. W.R. Cross: Financial Interests, Personal, Invited Speaker, Speaker fee: Myriad Genetics, Janssen, Astellas;Financial Interests, Personal, Advisory Board, Advisory Board fee: Bayer;Financial Interests, Institutional, Research Grant, Research grant: Myriad Genetics. S. Gillessen: Financial Interests, Personal, Advisory Board, 2018: Sanofi, Roche;Financial Interests, Personal, Advisory Board, 2018, 2019: Orion;Financial Interests, Personal, Invited Speaker, 2019 Speaker's Bureau: Janssen Cilag;Financial Interests, Personal, Advisory Board, 2020: Amgen;Financial Interests, Personal, Invited Speaker, 2020: ESMO;Financial Interests, Personal, Other, Travel Grant 2020: ProteoMEdiX;Financial Interests, Institutional, Advisory Board, 2018, 2019, 2022: Bayer;Financial Interests, Institutional, Advisory Board, 2020: Janssen Cilag, Roche, MSD Merck Sharp & Dohme, Pfizer;Financial Interests, Institutional, Advisory Board, 2018: AAA International, Menarini Silicon Biosystems;Financial Interests, Institutional, Advisory Board, 2019, 2020: Astellas Pharma;Financial Interests, Institutional, Advisory B ard, 2019: Tolero Pharmaceuticals;Financial Interests, Personal, Invited Speaker, 2021, 2022: SAKK, DESO;Financial Interests, Institutional, Advisory Board, 2021: Telixpharma, BMS, AAA International, Novartis, Modra Pharmaceuticas Holding B.V.;Financial Interests, Institutional, Other, Steering Committee 2021: Amgen;Financial Interests, Institutional, Advisory Board, 2021, 2022: Orion, Bayer;Financial Interests, Personal, Invited Speaker, 2021: SAKK, SAKK, SAMO - IBCSG (Swiss Academy of Multidisciplinary oncology);Financial Interests, Personal, Advisory Board, 2021: MSD Merck Sharp & Dhome;Financial Interests, Personal, 2021: RSI (Televisione Svizzera Italiana);Financial Interests, Institutional, Invited Speaker, 2021: Silvio Grasso Consulting;Financial Interests, Institutional, Other, Faculty activity 2022: WebMD-Medscape;Financial Interests, Institutional, Advisory Board, 2022: Myriad genetics, AstraZeneca;Financial Interests, Institutional, Invited Speaker, 2022: TOLREMO;Financial Interests, Personal, Other, Travel support 2022: AstraZeneca;Financial Interests, Institutional, Funding, 2021, Unrestricted grant for a Covid related study as co-investigator: Astellas;Non-Financial Interests, Advisory Role, 2019: Menarini Silicon Biosystems, Aranda;Non-Financial Interests, Advisory Role, Continuing: ProteoMediX. C. Pezaro: Financial Interests, Personal, Advisory Board, Ad board Dec 2020: Advanced Accelerator Applications;Financial Interests, Personal, Advisory Board, Aug 2021: Astellas;Financial Interests, Personal, Advisory Board, Oct 2021: Bayer;Financial Interests, Personal, Invited Speaker, Sept-Oct 2020: AstraZeneca;Financial Interests, Personal, Invited Speaker, Oct 2020: Janssen;Financial Interests, Personal, Advisory Board, July-Sept 2022: Pfizer. Z. Malik: Financial Interests, Personal, Advisory Board, advisry board for new hormonal therapy for breast cancer: sanofi;Financial Interests, Institutional, Invited Speaker, research grant for CHROME study: sanofi;Other, Other, support to attend meetings or advisory boards in the past: Astellas,Jaansen,Bayer;Other, Other, Sponsorship to attend ASCO meeting 2022: Bayer. M.R. Sydes: Financial Interests, Personal, Invited Speaker, Speaker fees at clinical trial statistics training sessions for clinicians (no discussion of particular drugs): Janssen;Financial Interests, Personal, Invited Speaker, Speaker fees at clinical trial statistics training session for clinicians (no discussion of particular drugs): Eli Lilly;Financial Interests, Institutional, Research Grant, Educational grant and drug for STAMPEDE trial: Astellas, Janssen, Novartis, Pfizer, Sanofi;Financial Interests, Institutional, Research Grant, Educational grant and biomarker costs for STAMPEDE trial: Clovis Oncology. L.C. brown: Financial Interests, Institutional, Research Grant, £170k educational grant for the FOCUS4-C Trial from June 2017 to Dec 2021: AstraZeneca;Financial Interests, Institutional, Funding, Various grants awarded to my institution for work undertaken as part of the STAMPEDE Trial: janssen pharmaceuticals;Non-Financial Interests, Other, I am a member of the CRUK CERP funding advisory panel and my Institution also receive grant funding from CRUK for the STAMPEDE and FOCUS4 trials: Cancer Research UK. M.K. Parmar: Financial Interests, Institutional, Full or part-time Employment, Director at MRC Clinical Trials Unit at UCL: Medical Research Council Clinical Trials Unit at UCL;Financial Interests, Institutional, Research Grant: AstraZeneca, Astellas, Janssen, Clovis;Non-Financial Interests, Advisory Role, Euro Ewing Consortium: University College London;Non-Financial Interests, Advisory Role, rEECur: University of Birmingham;Non-Financial Interests, Advisory Role, CompARE Trial: University of Birmingham. N.D. James: Financial Interests, Personal, Advisory Board, Advice around PARP inhibitors: AstraZeneca;Financial Interests, Personal, Advisory Board, Prostate cancer therapies: Janssen, Clovis, Novartis;Financial Interests, Institutional, Expert Testimony, Assisted with submissions regarding licencing for abiraterone: Janssen;Financial Interests, Personal, Advisory Board, Docetaxel: Sanofi;Financial Interests, Institutional, Expert Testimony, Providing STAMPEDE trial data to facilitate licence extensions internationally for docetaxel: Sanofi;Financial Interests, Personal, Advisory Board, Bladder cancer therapy: Merck;Financial Interests, Personal, Advisory Board, Advice around novel hormone therapies for prostate cancer: Bayer;Financial Interests, Personal, Invited Speaker, Lecture tour in Brazil August 2022 - speaking on therapy for advanced prostate cancer: Merck Sharp & Dohme (UK) Limited;Financial Interests, Institutional, Invited Speaker, Funding for STAMPEDE trial: Janssen, Astellas;Financial Interests, Institutional, Invited Speaker, Funding for RADIO trial bladder cancer: AstraZeneca. All other authors have declared no conflicts of interest.
ABSTRACT
On behalf of Grupo Oncoclínicas. Objectives: COVID-19 has become one of the worst pandemics in history and patients with acute myeloid leukemia (AML) seems to have high risk for severe events and death by the SARS-COV-2. Our aim is to report a survey conducted with Brazilian hematologists who attended AML patients with COVID-19 to evaluate the mortality rate and any potential risk factor for death. Methods: From May 5th to May 19th, 2021 we conducted a survey with 178 hematologists and collected data about adult patients with AML who had the COVID-19 diagnosis confirmed by RT-PCR: age, gender, possible source of contamination by SARS-COV-2 previous vaccination, moment of the AML treatment, status of AML when COVID was diagnosed and the outcomes related to COVID-19. Results: 33 patients (22 females) were recorded and the median age at the COVID-19 diagnosis was 60 years (19 to 79y). Only one had been previously vaccinated. In 21 cases (63%) in-hospital transmission was presumed to be the source of infection. In 20 patients (60,6%) COVID-19 was diagnosed when the patient had active AML, while in 13 patients (39,3%) AML was in remission. Twelve patients had diagnosis before starting AML treatment, 6 during intensive chemo induction remission, 3 during intensive chemo consolidation, 9 while in low-intensity therapy and 2 during treatment of relapse. There were 18 deaths attributed to COVID-19 (54,5%), of which 15 (83%) had active AML and 3 (17%) were in AML remission (p = 0.0052). We did not identify any other factors that could be associated to death. Among the 15 patients who survived 8 (53%) had some delay in their AML treatment. Discussion: Despite its limitations, this exploratory report addressing specifically AML and COVID-19 brings up some points to consider: 1) Most patients were presumed to be infected in the hospital, which reinforces the need for taking measures to control the dissemination of COVID-19 in the hospital enviroment.2) Our data suggests that patients with active AML possibly have a higher risk of death from COVID-19 and that patients on treatment did not have better outcomes. Beside this, 5 of 12 patients who had COVID-19 diagnosis before beginning AML treatment were alive. These findings lead us to speculate that the best strategy could be postponing the beginning of AML treatment as long as it is safe. 3) Our survey seems to confirm the high risk of death due to COVID-19 in patients with AML. 4) More than 50% of patients who survived COVID-19 had a delay in their treatment;the impact of this delay on AML survival remains uncertain and should be evaluated in future studies. Conclusion: AML patients seem to have a very high risk of death when infected by SARS-COV-2. Furthermore, even when recovered from COVID-19 those patients may suffer a delay in their treatment. Further reports are need to formulate evidence-based recommendations.
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Introduction & Objectives: The HoLERBT (Holmium Laser En-bloc Resection) has emerged as an alternative to classical TURBT (Transurethral Resection of Bladder Tumor) by using the en-bloc tumor resection technique. So far, the tumors in previous studies were mostly <3cm. We performed a previous pilot study with tumors >3cm (3-8cm) submitted to HoLERBT in 2019. All samples had detrusor muscle present and there were no peri-operative complications. These results support the present study to establish the best approach to endoscopic treatment of large bladder tumors. The objectives are to analyze differences between HoLERBT and TURBT in terms of presence of detrusor muscle in the histopathological analysis, intra-operative and peri-operative complications and oncological outcomes in large bladder tumors. Materials & Methods: This is a single-institution, randomized, single-blinded, prospective, controlled trial (RCT). The expected duration is of 24 months. The sample size calculated is 47 patients per group (n = 94). The study was approved by the Institutional Ethical Board and was submitted to the Brazilian Registry of Clinical Trials (ReBEC). Inclusion criteria is bladder tumor >3cm by CT or MRI. The exclusion criteria are diagnosis of invasive tumor on image examination (CT, MRI), urethral stenosis, systemic or intra-vesical chemotherapy or previous radiotherapy. The outcomes analyzed are quality of detrusor muscle, intra-operative and immediate post-operative complications, length of hospital stay (LOS);clinical progression, recurrence-free, overall and cancer-specific survival at 24 months. Results: This is an ongoing trial that began in January 2020, was suspended for 5 months due to Covid-19, restarted recruitment in September 2020 and currently has 9 patients in the group HoLERBT and 11 patients in the group TURBT. The first surgery was in 01/21/20. The current data represents 22% of the estimated sample and the analysis is partial. The median age (years) was 55.8 (29-83) and 65.5 (46-84), the median tumor size (cm) was 3.4 (2.1-5.4) and 3.1 (2.1-5.7), the median time of surgery (min) was 29 (16-49) and 37.6 (13-60), the LOS (days) was 1.25 (1-3) and 2.0 (1-4), complications rates Clavien I was 11% and 36% and Clavien >I was 0% and 9% for HoLERBT and TURBT. The presence of detrusor was 80% in both groups. The interim analysis will be made with 50% of the sample estimated to occur in June 2021 and the final analysis with 2 years of follow up is estimated to occur in January 2023. Conclusions: This is a RCT comparing HoLERBT and TURBT evolving large tumors, with a 2-year follow-up proposal. The initial analysis give support to continue the study in order to assess the real role of laser resection in high volume bladder tumor.
ABSTRACT
text: Background/Introduction: Chronic Myelomonocytic Leukemia (CMML) is an uncommon MDS/MPN overlap syndrome that has historically been included under the umbrella of myelodysplastic syndromes (MDS) for clinical trial and treatment. As a result, DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine have been the established standard of care for the treatment of CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver so treatment has required intravenous infusion or subcutaneous injections daily for 5-7 days every month (m) adding significant burden to older cancer patients due to daily time commitment and travel to treatment centers. In the context of pandemic SARS-CoV-2, parenteral therapy also increases contact with medical settings with increased infection risk. Oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed dose combination of decitabine and the CDA inhibitor cedazuridine that produced equivalent exposure (99%;90% CI 93% to 106%) to IV decitabine 20 mg/m 2 in a randomized cross-over study (Garcia-Manero et al, ASH 2019), and Median overall survival (mOS) for the entire study population in the ASCERTAIN study was approximately 32 months (Savona, 2021). Here, we present outcome data for this study for the enrolled subpopulation of patients with CMML. Methods: We used a randomized cross over design in which patients were randomized in the first 2 cycles 1:1 to either Sequence A: (decitabine 35 mg/ cedazuridine 100 mg in Cycle 1 followed by IV decitabine at 20 mg/m 2 in Cycle 2), or Sequence B: (IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2). We conducted an intra-patient comparison of decitabine PK (primary PK endpoint: decitabine AUC equivalence over 5 days of dosing). Cycles were repeated every 28 days (unless delays were needed). All patients received oral decitabine/cedazuridine in Cycles 3 and above until disease progression or unacceptable toxicity. Patients were eligible per the FDA-approved label of IV decitabine (MDS patients by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk patients). Clinical endpoints were best response according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, overall survival, and safety. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Results: Of the 133 patients enrolled and treated in ASCERTAIN, 16 (12%) had a diagnosis of CMML with demographics and as follows: median age 71.5 years, 69% Male/31% Female, median weight 87kg (range 65-124), 25% ECOG 0, 75% ECOG 1. Population disease characteristics were: 19% poor or intermediate risk cytogenetics, with median baseline hemoglobin 90 g/L, neutrophils 1.27 X 10 9/L, platelets 84 x 10 9/L, bone marrow blasts 5%, with 38% RBC transfusion dependent. Patients received a median of 7 cycles of therapy (range 3-24). Treatment-emergent adverse events of CTCAE Grade 3 or higher in > 10% of patients, independent of relationship to ASTX727, were cytopenias (neutropenia [69%], thrombocytopenia [63%], anemia [56%], leukopenia [19%]), febrile neutropenia (31%), fatigue (13%). Two patients (12.5%) had Complete Responses (CR), 8 (50%) had marrow CR ([mCR], including 3 (19%) with hematologic improvement (HI);Overall Response rate (ORR) [CR + PR+ mCR + HI] was 75%. Of six patients with baseline RBC transfusion dependence 3 (50%) became transfusion independent. Leukemia-free survival was 28.2 months and after a median follow up of more than 33 months, median overall survival had not been reached. Two patients (13%) went on to Hematopoietic Stem Cell Transplant (HCT). Conclusions: In the overall study, oral decitabine/cedazuridine delivered equivalent PK exposure to 5 days of IV decitabine 20mg/m 2 with a resultant clinical activity safety and efficacy profile in CMML patients consistent with the published literature (e.g Zeidan, et a 2017) and the Phase 2 experience. The use of oral decitabine/cedazuridine is a reasonable approach in CMML patients. References: Garcia-Manero, et al ASH 2019 Savona, et al, Int. MDS Symposium, 2021 Zeidan, et al, Cancer 2017: 3754-3762. [Formula presented] Disclosures: Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees;CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees;BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees;NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees;Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees;Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees;Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees;TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;ALX Oncology: Research Funding;Astex: Research Funding;Incyte: Research Funding. McCloskey: Pfizer: Consultancy;Takeda: Consultancy, Speakers Bureau;Incyte: Speakers Bureau;Novartis: Consultancy;COTA: Other: Equity Ownership;BMS: Honoraria, Speakers Bureau;Amgen: Speakers Bureau;Jazz: Consultancy, Speakers Bureau. Griffiths: Boston Biomedical: Consultancy;Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding;Abbvie: Consultancy, Honoraria;Taiho Oncology: Consultancy, Honoraria;Genentech: Research Funding;Astex Pharmaceuticals: Honoraria, Research Funding;Takeda Oncology: Consultancy, Honoraria;Novartis: Honoraria;Apellis Pharmaceuticals: Research Funding;Alexion Pharmaceuticals: Consultancy, Research Funding. Yee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Forma Therapeutics: Research Funding;Geron: Research Funding;Shattuck Labs: Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees;F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding;AbbVie: Honoraria;Janssen: Research Funding;Onconova: Research Funding;Genentech: Research Funding;Otsuka: Membership on an entity's Board of Directors or advisory committees;MedImmune: Research Funding;Jazz: Research Funding;Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding;Tolero: Research Funding;Takeda: Membership on an entity's Board of Directors or advisory committees;TaiHo: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees;Paladin: Membership on an entity's Board of Directors or advisory committees. Zeidan: BeyondSpring: Consultancy;Janssen: Consultancy;Boehringer Ingelheim: Consultancy, Research Funding;BioCryst: Other: Clinical Trial Committees;AstraZeneca: Consultancy;Pfizer: Other: Travel support, Research Funding;Kura: Consultancy, Other: Clinical Trial Committees;Incyte: Consultancy, Research Funding;Ionis: Consultancy;Daiichi Sankyo: Consultancy;Epizyme: Consultancy;Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding;Loxo Oncology: Consultancy, Other: Clinical Trial Committees;Genentech: Consultancy;Geron: Other: Clinical Trial Committees;Cardiff Oncology: Consultancy, Other: Travel support, Research Funding;BMS: Consultancy, Other: Clinical Trial Committees, Research Funding;Gilead: Consultancy, Other: Clinical Trial Committees;Aprea: Consultancy, Research Funding;Astellas: Consultancy;Astex: Research Funding;Jazz: Consultancy;Jasper: Consu tancy;Amgen: Consultancy, Research Funding;Agios: Consultancy;ADC Therapeutics: Research Funding;Acceleron: Consultancy, Research Funding;AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Al-Kali: Novartis: Research Funding;Astex: Other: Research support to institution. Patel: Agios: Membership on an entity's Board of Directors or advisory committees;Celgene-BMS: Membership on an entity's Board of Directors or advisory committees;PVI: Honoraria. Sabloff: Takeda: Membership on an entity's Board of Directors or advisory committees;BMS: Membership on an entity's Board of Directors or advisory committees;Astellas: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;TaiHo: Membership on an entity's Board of Directors or advisory committees;Jaxx: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees;ROCHE: Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees. Dao: Astex Pharmaceuticals, Inc.: Current Employment. Fazal: Janssen Oncology: Consultancy, Honoraria, Speakers Bureau;Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau;Gilead Sciences: Consultancy, Honoraria, Speakers Bureau;Novartis: Consultancy, Honoraria, Speakers Bureau;Agios: Consultancy, Honoraria, Speakers Bureau;Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau;Takeda: Consultancy, Honoraria, Speakers Bureau;Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau;AMGEN: Consultancy, Honoraria, Speakers Bureau;Incyte: Consultancy, Honoraria, Speakers Bureau;Jazz Pharmaceuticals:Consultancy, Honoraria, Speakers Bureau;Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau;Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau;Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau. Odenike: Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding;AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy. Kantarjian: Ipsen Pharmaceuticals: Honoraria;Astra Zeneca: Honoraria;Astellas Health: Honoraria;Aptitude Health: Honoraria;Pfizer: Honoraria, Research Funding;Novartis: Honoraria, Research Funding;Jazz: Research Funding;Immunogen: Research Funding;Daiichi-Sankyo: Research Funding;BMS: Research Funding;Ascentage: Research Funding;Amgen: Honoraria, Research Funding;AbbVie: Honoraria, Research Funding;KAHR Medical Ltd: Honoraria;NOVA Research: Honoraria;Precision Biosciences: Honoraria;Taiho Pharmaceutical Canada: Honoraria. DeZern: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roboz: Janssen: Research Funding;AbbVie: Consultancy;Actinium: Consultancy;Agios: Consultancy;Amgen: Consultancy;Astex: Consultancy;Astellas: Consultancy;AstraZeneca: Consultancy;Bayer: Consultancy;Blueprint Medicines: Consultancy;Bristol Myers Squibb: Consultancy;Celgene: Consultancy;Daiichi Sankyo: Consultancy;Glaxo SmithKline: Consultancy;Helsinn: Consultancy;Janssen: Consultancy;Jasper Therapeutics: Consultancy;Jazz: Consultancy;MEI Pharma - IDMC Chair: Consultancy;Mesoblast: Consultancy;Novartis: Consultancy;Otsuka: Consultancy;Pfizer: Consultancy;Roche/Genentech: Consultancy. Busque: Novartis: Consultancy. Leber: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Pfizer: Membership on an entity's Board of Directors or advisory committees, peakers Bureau;BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees.
ABSTRACT
[Formula presented] Background/Introduction: Lower-risk (IPSS low risk and Int-1) myelodysplastic syndromes (MDS) are typically treated supportively to address cytopenias. DNA methyltransferase inhibitors (DNMTi) such as azacitidine and decitabine (DEC) are FDA-approved for higher risk MDS patients (pts), and while the DEC USPI includes IPSS Int-1 pts, it is not widely used in this population. Approved intravenous (IV) or subcutaneous (SC) regimens require 5-7 days of treatment every month burdening older cancer pts due to daily travel and treatment time and may increase potential risk from pandemic SARS-CoV-2 infection. Because DNMTis are rapidly degraded by cytidine deaminase (CDA) in the gut and liver, oral availability has only been recently possible. A randomized study with CC-486, an oral formulation of azacitidine, in the Int-1 population showed a median overall survival (mOS) of approximately 17 months for both placebo and treated patients (Garcia-Manero, 2021). Oral DEC 35 mg/cedazuridine 100 mg (ASTX727) or DEC-C, is an oral fixed dose combination (FDC) of DEC and the CDA inhibitor cedazuridine (CED) resulting in equivalent exposure (99%;90% CI 93% to 106%) to standard IV DEC 20 mg/m 2 for 5 days in an intra-patient randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present data on patients with lower risk MDS from that study. Methods: We used a randomized cross over design with pts randomized 1:1 in the first 2 cycles to either Sequence A: (DEC 35 mg/ CED 100 mg in Cycle 1 and IV DEC at 20 mg/m 2 in Cycle 2), or Sequence B (IV DEC in Cycle 1 and oral DEC/CED in Cycle 2). Cycles were repeated every 28 days unless delays were needed, and all patients received oral DEC-C in Cycles 3+ until disease progression or unacceptable toxicity. We conducted an intra-patient comparison of DEC PK (DEC AUC equivalence over 5 days of dosing). Pts were eligible as per the FDA-approved label of IV DEC (MDS pts by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk pts). Clinical endpoints were best response as assessed by an independent expert panel according to IWG 2006 response criteria, transfusion independence (TI), overall survival (OS), and safety. Results: Of the 133 pts treated in ASCERTAIN, 69 had a diagnosis of lower-risk MDS (93% Int-1, 7% LR). Median age was 70.0 years (range 45-87), 65% were male, median weight was 84 kg (range 50-127), median baseline hematologic parameters were: hemoglobin 89 g/L (range 69.8-146.5), WBCs 1.50 X 10 9/L (range 0.11-7.1), platelets (plt) 86 x 10 9/L (range 5-703), bone marrow blasts 4% (range 0-18), cytogenetics: 7 (10.1%) poor-risk, 21 (30.4%) intermediate risk, 37 (53.6%) better-risk, 4 (5.7%) missing or not evaluable. 27(39%) of the pts were RBC transfusion dependent (TD) and 6 (9%) plt TD. 17 (25%) had received prior MDS treatment, 3% prior DNMTi. Pts received a median of 9 cycles of therapy (range 1-28). Treatment-emergent adverse events of CTCAE Gr 3 or higher in >10% of pts, independent of relationship to ASTX727, included cytopenias (neutropenia [59%], thrombocytopenia [58%], anemia [48%], leukopenia [26%]), febrile neutropenia (32%), and pneumonia (19%). Sixteen pts (23%) achieved Complete Response (CR), 18 (26%) had marrow CR (mCR), including 9 (13%) with hematologic improvement (HI). Overall Response rate (ORR;CR + PR+ mCR + HI) was 57%. Of those RBC or plt TD at baseline, 13 (48%) became RBC TI and 4 (67%) became plt TI. With approximately 32 months of median follow up, neither median leukemia-free survival (mLFS) nor mOS had been reached (Figure 1). Twelve pts (17%) went on to allogeneic stem cell transplant. Conclusions: Oral decitabine/cedazuridine given as a FDC in MDS pts produced equivalent PK exposure to 20 mg/m 2 IV DEC;in lower risk MDS pts with treatment indicated, the agent was generally well-tolerated with prolonged treatment and could result in mLFS and mOS which exceeds 32 months. This FDC and other dosing regimens of oral DEC-C should be further studied in this patient population. References: Garcia-Mane o, et al, ASH 2019 Savona, et al, Int. MDS Symp. 2021 Garcia-Manero, et al, Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients with Lower-Risk Myelodysplastic Syndromes. J.Clin.Onc. 2021 39:13, 1426-1436 [Formula presented] Disclosures: McCloskey: Pfizer: Consultancy;Jazz: Consultancy, Speakers Bureau;COTA: Other: Equity Ownership;Incyte: Speakers Bureau;Takeda: Consultancy, Speakers Bureau;Novartis: Consultancy;BMS: Honoraria, Speakers Bureau;Amgen: Speakers Bureau. Griffiths: Alexion Pharmaceuticals: Consultancy, Research Funding;Abbvie: Consultancy, Honoraria;Taiho Oncology: Consultancy, Honoraria;Genentech: Research Funding;Novartis: Honoraria;Takeda Oncology: Consultancy, Honoraria;Astex Pharmaceuticals: Honoraria, Research Funding;Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding;Apellis Pharmaceuticals: Research Funding;Boston Biomedical: Consultancy. Yee: Paladin: Membership on an entity's Board of Directors or advisory committees;TaiHo: Membership on an entity's Board of Directors or advisory committees;Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Genentech: Research Funding;Geron: Research Funding;Janssen: Research Funding;Jazz: Research Funding;MedImmune: Research Funding;Onconova: Research Funding;Tolero: Research Funding;AbbVie: Honoraria;Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees;Otsuka: Membership on an entity's Board of Directors or advisory committees;Shattuck Labs: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding;Forma Therapeutics: Research Funding;Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zeidan: Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding;Genentech: Consultancy;Ionis: Consultancy;Astellas: Consultancy;Epizyme: Consultancy;AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding;Jasper: Consultancy;Cardiff Oncology: Consultancy, Other: Travel support, Research Funding;BeyondSpring: Consultancy;Loxo Oncology: Consultancy, Other: Clinical Trial Committees;Janssen: Consultancy;Acceleron: Consultancy, Research Funding;AstraZeneca: Consultancy;Kura: Consultancy, Other: Clinical Trial Committees;Gilead: Consultancy, Other: Clinical Trial Committees;Agios: Consultancy;Daiichi Sankyo: Consultancy;Boehringer Ingelheim: Consultancy, Research Funding;Geron: Other: Clinical Trial Committees;BMS: Consultancy, Other: Clinical Trial Committees, Research Funding;BioCryst: Other: Clinical Trial Committees;Pfizer: Other: Travel support, Research Funding;Aprea: Consultancy, Research Funding;ADC Therapeutics: Research Funding;Jazz: Consultancy;Incyte: Consultancy, Research Funding;Amgen: Consultancy, Research Funding;Astex: Research Funding. Al-Kali: Astex: Other: Research support to institution;Novartis: Research Funding. Patel: Celgene-BMS: Membership on an entity's Board of Directors or advisory committees;PVI: Honoraria;Agios: Membership on an entity's Board of Directors or advisory committees. Sabloff: Pfizer: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;Astellas: Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;ROCHE: Membership on an entity's Board of Directors or advisory committees;TaiHo: Membership on an entity's Board of Directors or advisory committees;Jaxx: Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory ommittees;BMS: Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees. Dao: Astex Pharmaceuticals, Inc.: Current Employment. Fazal: Taiho Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau;Stemline Therapeutics: Consultancy, Honoraria, Speakers Bureau;Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau;Novartis: Consultancy, Honoraria, Speakers Bureau;Karyopharm Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau;Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau;Janssen Oncology: Consultancy, Honoraria, Speakers Bureau;Incyte: Consultancy, Honoraria, Speakers Bureau;Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau;Gilead Sciences: Consultancy, Honoraria, Speakers Bureau;Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau;AMGEN: Consultancy, Honoraria, Speakers Bureau;Agios: Consultancy, Honoraria, Speakers Bureau;Takeda: Consultancy, Honoraria, Speakers Bureau. Odenike: AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy;Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding. Kantarjian: AbbVie: Honoraria, Research Funding;Novartis: Honoraria, Research Funding;Ascentage: Research Funding;Pfizer: Honoraria, Research Funding;BMS: Research Funding;Daiichi-Sankyo: Research Funding;Amgen: Honoraria, Research Funding;Ipsen Pharmaceuticals: Honoraria;Jazz: Research Funding;Astellas Health: Honoraria;Immunogen: Research Funding;Astra Zeneca: Honoraria;Aptitude Health: Honoraria;KAHR Medical Ltd: Honoraria;NOVA Research: Honoraria;Precision Biosciences: Honoraria;Taiho Pharmaceutical Canada: Honoraria. DeZern: Takeda: Consultancy, Membership on an entity's Board of Directors or advisorycommittees;Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roboz: Novartis: Consultancy;Mesoblast: Consultancy;Jasper Therapeutics: Consultancy;Jazz: Consultancy;MEI Pharma - IDMC Chair: Consultancy;Daiichi Sankyo: Consultancy;Otsuka: Consultancy;Bristol Myers Squibb: Consultancy;Blueprint Medicines: Consultancy;Bayer: Consultancy;AstraZeneca: Consultancy;Astellas: Consultancy;Astex: Consultancy;Amgen: Consultancy;Agios: Consultancy;Actinium: Consultancy;AbbVie: Consultancy;Janssen: Research Funding;Celgene: Consultancy;Glaxo SmithKline: Consultancy;Helsinn: Consultancy;Janssen: Consultancy;Pfizer: Consultancy;Roche/Genentech: Consultancy. Busque: Novartis: Consultancy. Leber: Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Otsuka: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;TaiHo: Honoraria, Membership on an entity's Board of Directors or advisory committees;AMGEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Cons ltancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees;CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees;BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees;NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees;Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees;Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees;Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees;TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;ALX Oncology: Research Funding;Astex: Research Funding;Incyte: Research Funding.
ABSTRACT
Purpose or Objective To evaluate the influence of Charlson comorbidity index (CCI) in survival outcomes in patients (pts) with lung cancer (LC) treated with concomitant radiochemotherapy (RCT) or radiotherapy (RT) alone with radical intention during SARS-2-COVID19 pandemic. Materials and Methods Retrospective study of 50 pts with LC treated with radical intention from November 2019 to December 2020 in University Hospital of Badajoz and University Hospital Virgen Macarena in Seville. All pts were treated with radical intention and hypofractionated scheme of radiotherapy (total dose 55 Gy in 20 fractions of 2.75 Gy/daily) to decrease the duration of thoracic radiotherapy in pandemic era. 40% of pts were treated with concomitant RCT, 38% with RT alone and 22% with chemotherapy and sequential RT. CCI was used to identify associated diseases in all pts, after the evaluation of 19 items that influence in the life expectancy of them. In general, it is considered low comorbidity ≤ 3 points in CCI and high comorbidity > 3 points. Kaplan-Meier curves have been used for the statistical analysis of overall survival (OS) and cancer specific survival (CSS) and log-rank test to compare them. Results In the study, 24 pts had ≤ 3 points in CCI (48%) and 26 pts had > 3 points (52%). Mean CCS in pts with CCI≤ 3 points was 18.5 months and in pts with CCI > 3 points was 13 months. 15-months CSS was 83.3% in pts with CCI ≤ 3 points and 40.9% in pts with CCI > 3 points without statistically significant differences (p 0.755). Mean OS in pts with CCI≤ 3 points was 16.8 months and in pts with CCI > 3 points was 11.5 months.15-months OS was 74.3% in pts with CCI ≤ 3 points and 32% in pts with CCI > 3 points (p 0.620). Toxicity in both groups was similar without differences between pts with CCI ≤ 3 points and CCI > 3 points. Only one grade 3 oesophagitis was registered in CCI ≤ 3 points group. Conclusion The Charlson comorbidity index is a system that evaluates 10 years life expectancy. According to our results and despite the short follow-up, pts with CCI ≤ 3 points have better OS and CSS than pts with CCI > 3 points. In both groups, hypofractionated radiotherapy was well-tolerated regardless the CCI. Although more studies are needed, CCI can be an important factor to evaluate in patients with lung cancer because it identifies pts with a high probability of mortality. For this reason, this score can be an useful tool to assess the most suitable treatment option, especially in patients with several comorbidities.
ABSTRACT
BACKGROUND AND OBJECTIVES: Due to the inevitability of waiting time for surgery, this problem seems to have become more pronounced since the outbreak of COVID-19, and due to the high incidence of preoperative hydronephrosis in upper urinary tract urothelial carcinoma (UTUC) patients, it is particularly important to explore the impact of preoperative waiting time and hydronephrosis on upper urinary urothelial carcinoma. METHODS: 316 patients with UTUC who underwent radical surgery at a high-volume center in China between January 2008 and December 2019 were included in this study. We retrospectively collected the clinicopathologic data from the medical records, including age, sex, smoking history, ECOG performance status (ECOG PS), body mass index (BMI), tumor location and size, number of lesions, T stage, N stage, surgical approach and occurrence of hydronephrosis, lymph node invasion, lymph node dissection, surgical margin, tumor necrosis, infiltrative tumor architecture, lymphovascular invasion and concomitant bladder cancer. Surgical wait time was defined as the interval between initial imaging diagnosis and radical surgery of UTUC. Hydronephrosis was defined as abnormal dilation of the renal pelvis and calyces due to obstruction of the urinary system. Firstly, all patients were divided into short-wait (<31 days), intermediate-wait (31-90 days) and long-wait (>90 days) groups according to the surgical wait time. The clinicopathological characteristics of each group were evaluated and the survival was compared. For patients with hydronephrosis, we subsequently divided them into two groups: short-wait (≤60 days) and long-wait (>60 days) groups according to the surgical wait time. Univariate and multivariate COX regression analysis were performed to evaluate the prognostic risk factor for patients with hydronephrosis. RESULTS: A total of 316 patients with UTUC were included in this study with a median surgical wait time of 22 days (IQR 11-71 days). Of the 316 patients, 173 were classified into the short-wait group (54.7%), 69 into the intermediate-wait group (21.8%) and 74 into the long-wait group (23.5%). The median follow-up time for all patients was 43 months (IQR 28-67months). The median surgical wait times of the short-wait, intermediate-wait and long-wait group were12 days (IQR 8-17days), 42days (IQR 37-65days) and 191days (IQR 129-372days), respectively. The 5-year overall survival (OS) of all patients was 54.3%. The 5-year OS of short-wait, intermediate-wait and long-wait groups were 56.4%, 59.3% and 35.1%, respectively (P=0.045). The 5-year cancer-specific survival (CSS) of short-wait, intermediate-wait and long-wait groups were 65.8%, 70.9% and 39.6%, respectively (P=0.032). In the subgroup analysis, we divided 158 UTUC patients with hydronephrosis into short-wait group (≤60 days) and long-wait group (> 60 days), 120 patients were included in the short-wait group and 38 patients in the long-wait group. The median surgical wait times of the short-wait and long-wait group were 14days (IQR 8-28days) and 174days (IQR 100-369days), respectively. The 5-year OS of long-wait group was significantly lower than the OS of short-wait group (44.2% vs. 55.1%, P =0.023). The 5-year CSS of long-wait and short-wait group were 49.1% and 61.7%, respectively (P=0.041). In multivariate Cox regression analysis of UTUC patients with hydronephrosis, surgical wait time, tumor grade, pathological T stage, and tumor size were independent risk factors for OS and CSS. Lymph node involvement was also a prognostic factor for CSS. CONCLUSION: For patients with UTUC, the surgical wait time should be limited to less than 3 months. For UTUC patients with hydronephrosis, the OS and CSS of patients with surgical wait time of more than 60 days were relatively shorted than those of patients with surgical wait time of less than 60 days.